tbuckley/cabot-search huggingface dataset:
A phase 2 study of anlotinib in patients with metastatic pheochromocytoma/paraganglioma.
Authors: Anli Tong, YunYing Cui, Yinjie Gao, Yuejuan Cheng, Yuxiu Li
Journal: Journal of Clinical Oncology (2022)

e15000 Background: Metastatic pheochromocytoma / paraganglioma (MPP) are rare while the prognosis was poor and the efficacy for current therapy was unsatisfactory. Anlotinib is a multikinase inhibitor targeting tumor angiogenesis and growth. Currently, there is no study evaluating the efficacy and safety of anlotinib in MPP pts. Methods: This is a prospective, single-arm phase 2 trial (NCT 04860700). Pts with histologically or radiologically confirmed MPP were enrolled. Main other inclusion criteria were 18-75 years old and ECOG PS 0-2. Anlotinib (8-12mg, QD) were given orally from d1 to d14 every 21 days until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included biochemical (catecholamine levels) response rate (BRR), progression-free survival (PFS) and safety. Results: 10 pts with MPP were enrolled and tumor response were evaluated in 6 patients. All these 6 patients had objective radiological evidence of progression within 6 months before enrollment. Tumor shrinkage was observed in 4 pts, 1 achieved partial response (PR) and 3 achieved stable disease (SD). The ORR was 16.7% (1/6). For 1 patient (p-1) with no measurable lesions, the pathological lymph nodes shrunk obviously and the rapid progression of bone metastatic lesion was well controlled. Among all 6 pts, catecholamine levels were obviously decreased in 4 pts, achieving a BRR of 67%. 1 patient who developed blindness at right eye caused by the progression of intracranial metastasis after chemotherapy had recovered the vision after anlotinib treatment. At the data cutoff date on February 1st, 2022, 1 patient terminated anlotinib since obvious elevation of catecholamine level and others were still in treatment with no radiographic disease progression. The median treatment duration was 7.5 cycles. The details of efficacy result were listed in table below. Overall, treatment of anlotinib blocked the rapid disease progression and achieved a durable disease control. The most common treatment-related adverse event (TRAE) was hypertension (5/6), which was well controlled, other TRAEs occurred in &gt; 1 pts included grade 1 or 2 proteinuria (2/6) and palmar-plantar erythrodysesthesia syndrome (2/6). Conclusions: The preliminary results of this study indicated that anlotinib is a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. Clinical trial information: NCT04860700. [Table: see text]
Geographical distribution of prostate cancer clinical trials across the United States.
Authors: Fnu Amisha, Sunny R K Singh, Paras Malik, Amudha Kumar, Manojna Konda, SunilKumar Kakadia, Sindhu Janarthanam Malapati
Journal: Journal of Clinical Oncology (2022)

e18561 Background: Prostate cancer is the second leading cause of cancer-related mortality among males in the United States after lung cancer. Among other factors, physical access to clinical trial site plays a pivotal role in the recruitment process and hence impact outcomes. We aim to study the geographical distribution of phase III and IV prostate cancer clinical trials in the United States. Methods: The United States Cancer Statistics Data Visualisation Tool was utilised to estimate the number of new cases of prostate cancer for the latest available years i.e., 2014-2018. An extensive search was carried out at ClinicalTrials.gov registry using advanced search fields – disease (prostate cancer), sex (male), study type (clinical trial), phase (III and IV), country (United States) and study start (from 01/01/2014 to12/31/2018). The trials which were terminated, withdrawn, or suspended were excluded from the study. Both these tools were further explored to provide state-wise distribution of new trials and cases. Results: Between 2014-2018 in the United States, 997, 454 new prostate cancer cases were reported and 59 phase III &amp; IV clinical trials were made available across 51 states. The average number of new prostate cancer cases and trials per state was 19,558 and 17 (range 45-0) respectively. The states with maximum reported number of new cases were California, New York, Florida, and Texas. These accounted for 30.2% of total cases and only 15.5% of total trials. The states with least reported new cases were Alaska, Vermont, Wyoming, and North Dakota. These accounted for 0.84 % of total cases and 2% of total trials [Table]. The states with the minimum number of trials per case were Mississippi (0.00035), Texas (0.00041), Florida (0.00042), New York (0.00045) and California (0.00047) whereas the states with maximum number of trials per case were Alabama (0.2352), District of Colombia (0.0061), Alaska (0.0054) and Vermont (0.0024). Conclusions: Variation in the availability of phase III and IV clinical trials for newly diagnosed prostate cancer cases was noted across 51 states of the US during the study period from 2014-2018. The states with higher disease burden had a much lower ratio of trials available per case despite higher absolute number of clinical trials in comparison to the states with lower disease burden. This highlights the need for better geographical allocation of clinical trials in the future based on the cancer burden for efficient resource utilisation and improved healthcare delivery.[Table: see text]
Circulating tumor cells and vitamin D in primary breast cancer.
Authors: Michal Mego, Barbora Vlkova, Marian Karaba, Gabriel Minarik, Juraj Benca, Tatiana Sedlackova, Katarina Kalavska, Daniel Pindak, Jozef Mardiak, Peter Celec
Journal: Journal of Clinical Oncology (2022)

e12558 Background: Circulating tumor cells (CTCs) contributing to the metastatic cascade and represent an independent survival predictor in breast cancer (BC) patients. Vitamin D has pleiotropic effects and its low concentrations are associated with infections, cancer, but also other pathologic conditions. The aim of this study was to assess plasma vitamin D level in primary BC patients in relation to CTCs. Methods: This study included 91 non-metastatic breast cancer patients (stage I-III) with plasma samples available in the biobank of the National Cancer Institute in Slovakia. Blood samples for the analyses were drawn at the time of surgery. Peripheral blood mononuclear cells (PBMCs) were depleted of hematopoetic cells using RossetteSepTM negative selection kit. RNA extracted from CD45-depleted PBMCs was analyzed for the expression of transcription factors (TWIST1, SNAIL1, SLUG, ZEB1) that induce epithelial-to-mesenchymal transcription (EMT-TF) and epithelial ( CK19) gene transcripts using qRT-PCR. Patient samples with higher epithelial and/or mesenchymal gene transcripts than those of healthy donors (n = 60) were considered CTCs positive. Total 25-OH vitamin D was measured in plasma using ELISA. Results: CTCs were detected in 30 (33%) patients, 14 (15.4%) patients had detectable CTCs with epithelial characteristics, 13 (14.3%) patients had CTCs with an EMT phenotype, while peripheral blood of 3 (3.3%) patients exhibit both CTCs subtypes. Patients with detectable CTCs in peripheral blood had significantly lower vitamin D concentrations in comparison to patients without detectable CTCs (mean ± SD) 8.50 ± 3.89 µg/L for CTCs positive vs. 9.69 ± 3.49 µg/L for CTCs negative patients respectively, P = 0.03). There was no association between plasma vitamin D and other patient/tumor characteristics. At a median follow-up of 96.5 months (range: 8.4 - 109.4 months), 28 patients (30.8%) had experienced a progression and 24 patients (26.4%) had died. Patients with vitamin D above median had better overall survival (HR = 0.36, 95%CI 0.16 – 0.80, P = 0.017) compared to patients below median vitamin D. Conclusions: According to our knowledge, this is the first report of an association between plasma vitamin D concentrations and CTCs in primary breast cancer patients. We suggest that vitamin D could play a direct role in tumor dissemination and its supplementation might affect metastatic cascade. Alternatively, decreased vitamin D could be a consequence and hence a biomarker of a more invasive disease. Animal experiments and interventional studies are needed to prove the causality of the observed association.
Phase II study of lower-intensity frontline therapy for newly diagnosed patients with AML who are unfit or otherwise not eligible for frontline clinical trials.
Authors: Sangeetha Venugopal, Elias Jabbour, Naveen Pemmaraju, Guillermo Montalban-Bravo, Kelly Sharon Chien, Naval Guastad Daver, Nitin Jain, Jan Andreas Burger, Yesid Alvarado Valero, Abhishek Maiti, Courtney Denton Dinardo, Gautam Borthakur, Rashmi Malla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop M. Kantarjian, Tapan M. Kadia
Journal: Journal of Clinical Oncology (2022)

e19028 Background: Pts with newly diagnosed(ND) AML often present with abnormal organ function, poor performance status (PS), concurrent active malignancies, and active infections precluding them from enrolling on frontline clinical trials, since standard eligibility routinely exclude them. We designed a lower-intensity regimen of cladribine plus low-dose cytarabine (LDAC) alternating with decitabine with less stringent inclusion criteria in ND pts unfit or ineligible for existing clinical trials. Methods: Pts &gt;18 years with untreated AML and ineligible for other frontline AML clinical trials were enrolled (NCT01515527). Eligibility criteria included either creatinine ≥2mg/dL; or total bilirubin ≥2 mg/dL; active concurrent cancer, infection, or ECOG PS of 3 or 4; or ineligible for participation in a higher priority protocol. Induction was cladribine 5 mg/m 2 IV on D1-5, Cytarabine 20 mg SQ twice daily on D 1-10, followed by consolidation with cladribine 5 mg/m 2 IV on D1-3, Cytarabine 20 mg SQ twice daily on D 1-10 alternating with decitabine 20 mg/m 2 IV, daily on D 1-5. Primary objective was 60-d survival rate. Results: 25 pts have been enrolled. The median age was 73 yrs (range, 52-82) with 76% aged ≥70 yo. 6 pts (24%) had concurrent active malignancy, 4 (16%) had baseline creatinine &gt;2mg/dL, and 9 (36%) had PS ≥3. 76% were adverse risk per ELN 2017 (Table). Among 25 evaluable pts, 17 (68%) achieved a composite complete response (CRc) including 10 (40%) CR and 7 (28%) CR with incomplete count recovery (CRi). Among responders, 6 pts (35%) achieved MRD neg by flow. Of 7 pts with no response, all were ELN adverse risk. Median cycles to response was 1 (range: 1 - 4). 30- and 60 d mortality was 8% and 16%, respectively, including 2 pts (8%) who died due to pseudomonal sepsis on D8, and the other due to pneumonia on D11. At a median follow up of 9.4 months (range, 0.4- 19.9 m),median OS (6-mo OS% - 61 %), and EFS was 8.3 mo each (6-mo RFS% - 56 %) with a 60-d OS and EFS rate of 83% each, with a median RFS of 5.8 mo (2-mo RFS%-66%; 6-mo RFS% - 49 %). In this challenging patient population, this lower-intensity regimen was well tolerated, with an acceptable toxicity profile. Conclusions: In an unfit patient population of ND AML with high comorbidity burden, that were ineligible for other clinical trials, induction therapy with Cladribine plus LDAC was feasible and effective and can allow pts to achieve remission and move on to effective post-remission therapy. Clinical trial information: NCT01515527. [Table: see text]
Melanoma: Morphological essays of energetic tumor death under the influence of live mitochondria.
Authors: Alla I. Shikhlyarova, Elena M. Frantsiyants, Irina V. Kaplieva, Irina V. Neskubina, Natalia D. Cheryarina, Lidia K. Trepitaki, Ekaterina I. Surikova, Valeria A. Bandovkina, Yuriy V. Przhedetskiy, Viktoria V. Pozdnyakova, Viktoria Yu Przhedetskaya, Natalia A. Zakharova, Olga Khokhlova, Oleg I. Kit
Journal: Journal of Clinical Oncology (2022)

e21561 Background: Global trials form a new mitochondrial paradigm for suppressing the growth of malignant tumors. The unique role of mitochondria (MC) in the processes of metabolism, proliferation, and cell death was proven by the establishment of signaling pathways and critical conditions for the self-organization and degradation of MC. There are still many unsolved problems in the development of a new strategy, including the absence of an integral picture of morphological changes in the tumor under the influence of mitochondrial therapy (MCT), and this determined the purpose of the study. Methods: The study included male and female Balb/c Nude mice weighing 21-22 g. B16/F10 melanoma was transplanted to mice subcutaneously, and suspension of live liver MC was injected intraperitoneally. MC were isolated by differential centrifugation (Avanti J-E high-speed centrifuge, BECKMAN COULTER, USA). After an MCT cycle, the melanoma structure was examined with hematoxylin and eosin staining and light microscopy (LEICA DM LS2). Results: Control samples of melanoma (without MCT) showed abundant vascularization with dense growth of epithelial-like cells with branched cytoplasm, an eccentric nucleus and a moderate content of melanin pigment. Massive hypoxic death, autolysis and autoxidation of tumor cells were registered in male mice after MCT, as well as matrix hyalinosis, pronounced subcutaneous tissue edema with segregation and necrotization of fat accumulations. The formation of a large cavity filled with detritus indicated signs of total tumor necrosis and ischemia. The accumulation of hyperchromic granules indicated the activation of granulocytic and phagocytic elements in the mechanism of tumor regression. Female mice showed rare small areas of necrosis, as well as pronounced fragmentation of nuclei and cytoplasm of cells in most fields of view induced by bioenergetic hypoxia, with the formation of apoptotic bodies. Along the edge of the cells subjected to autophagocytosis, melanin accumulated as it left the cells and accumulated as large granules, while small ones filled the space of the vessels. The process of melanoma regression was confirmed by a significant increase in free fibrous areas, where only faint cell shadows remained. Conclusions: The initial state of melanoma degrades under the influence of MCT inducing bioenergetic hypoxia in male and female Balb/c Nude mice in different ways. Gender, in fact, hormonal differences determine the dominance of different ways of cell death, necrosis (in males) and apoptosis (in females), while maintaining the MCT access to the processes of preventing tumor growth.
Preliminary safety and efficacy of relmacabtagene autoleucel (relma-cel) as second-line therapy for primary refractory Chinese patients with large B-cell lymphoma (LBCL): Results from an open-label, multicenter, single-arm phase I study.
Authors: Zixun Yan, Yongxian Hu, Lingshuang Sheng, Li Wang, Shu Cheng, Wen Wu, Pengpeng Xu, Muchen Zhang, Chris Wang, Zisong Zhou, Su Yang, Yun Qin, He Huang, Weili Zhao
Journal: Journal of Clinical Oncology (2022)

e19509 Background: Relmacabtagene autoleucel (relma-cel) is a CD19-directed 4-1BB/CD3ζ chimeric antigen receptor T cell (CAR-T) product manufactured in China, it had been approved by NMPA for treatment of adults with r/r LBCL after ≥2 lines of systemic therapies based on the pivotal study (NCT04089215). Here, we report the results of relma-cel in patients with primary refractory disease after first-line standard of care (R-CHOP), an indication with poor clinical outcomes. Methods: This was an open-label, single-arm, multi-center, phase I study (NCT04812691). Eligible adults (≥18 years) met the criteria for primary refractory LBCL (not reach CR after first-line therapy). After screening and leukapheresis, patients received lymphodepletion [cyclophosphamide/fludarabine] followed by 100×10 6 CAR+ T cells. Results: High-risk disease characteristics were common in the study (Table). As of Nov 26, 2021, 14 patients had leukapheresis and 12 had relma-cel infusion. Among the efficacy-evaluable patients, the best ORR and CRR was 75.0% (95% CI: 42.8-94.5%) and 33.3% (95% CI: 9.9-65.1%), 3-month ORR and CRR were 41.7% (95% CI: 15.2-72.3%) and 33.3% (95% CI: 9.9-65.1%), respectively. With a median follow-up of 9.1 months, the median PFS was 10.0 months (95% CI: 0.85, NA), median DOR and OS were NA (95% CI: 2.2, NA) and NA (95% CI: 3.2, NA). Treatment-emergent adverse events (TEAE) were found in all patients. 10 (83.3%) patients had 1 or more study related Gr ≥3 TEAEs, the most common was cytopenia. 6 (50.0%) patients had Gr ≥3 prolonged cytopenia at Day 29. 6 (50.0%) patients had Gr ≤ 2 Cytokine Release Syndrome (CRS) with a median onset and duration of 6.0 and 11.0 days, no Gr ≥3 CRS observed. Neurotoxicity (NT) occurred in 2 patients (all Gr 1), the median onset and duration was 15.0 and 6.0 days. 2 deaths occurred in study due to disease progression. For 12 PK-evaluable patients, median Cmax was 36762.5 copies/μg DNA by qPCR with a median Tmax of 11 days and a median AUC1-29 of 333459.3 day×copies/μg. In 6 patients whose CAR-T cell had reached BLQ, 5 (83.3%) still had response with 4 (66.7%) patients for CR, 1 (16.7%) patients for PR. Univariate analysis did not indicate association between response and either exposure (AUC1–29) or peak concentration. Conclusions: Relma-cel was tolerable and showed promising ORR in Chinese patients with primary refractory LBCL. Evaluation of relma-cel in high risk second-line LBDL patients using a randomized trial design is planned. Clinical trial information: NCT04812691. [Table: see text]
Final clinical results of pivotal trial of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive CIS and papillary nonmuscle-invasive bladder cancer (NMIBC).
Authors: Karim Chamie, Sam S. Chang, Mark Gonzalgo, Eugene V. Kramolowsky, Wade J. Sexton, Paul Bhar, Sandeep K. Reddy, Patrick Soon-Shiong
Journal: Journal of Clinical Oncology (2022)

4508 Background: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL15RaFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase 1b data in BCG-naïve patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. Pembrolizumab was approved in 2020 with a 41% complete response (CR) rate in a single arm phase 2 trial of 96 patients. We report data on 160 subjects from an open-label, 3 cohort multicenter study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825). Methods: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A (CIS) is incidence of CR of CIS at any time. The primary endpoint for Cohort B (Papillary) is disease-free rate (DFS) at 12 months. Results: To date, we enrolled 160 patients (83 CIS, 77 Papillary). In the overall population, median age is 72.3 years, 81% male, with mean number of prior TURBT = 4. Median number of prior BCG doses = 12. CIS patients have a CR rate of 71% (59/83), with a mediation duration of CR of 24.1 months in responders; 91% avoided cystectomy and 96% 24 month bladder cancer specific progression free survival (defined as progression to MIBC). Papillary patients have a 57% 12 month DFS rate, 48% 24 month DFS rate, and 95% avoided cystectomy. Median time to cystectomy in responders (N = 4) is 12.9 months versus 7.8 in non-responders (N = 8) for a 5.1 month delay in cystectomy. PK data shows no systemic levels of N-803; activity is confined to the bladder. Low grade treatment related AEs (grade 1-2) include dysuria (22%), pollakiurua (19%), hematuria (18%), fatigue (16%), and urgency (12%), all other AEs were seen at 7% or less. No treatment related grade 4 or 5 AE were seen. No SAE's were considered treatment related. No immune related SAE's have been seen. Conclusions: In 160 patients with BCG-unresponsive NMIBC, there is a 99% bladder cancer specific overall survival at 2 years. In CIS patients 71% CR rate with 24.1 months median duration of response, and 53% DFS rate at 18 months in Papillary disease. Cystectomy was avoided in over 90% of patients with 2 years of follow-up. The efficacy and safety profile of N-803+BCG exceeds that of other available intravesical and systemic options for BCG-unresponsive NMIBC. Clinical trial information: NCT03022825.
Genomic profiling and the impact of MUC19 mutation in hepatoid adenocarcinoma of the stomach.
Authors: Mengxuan Zhu, Erbao Chen, Shan Yu, Chen Xu, Yiyi Yu, Xin Cao, Wei Li, Pengfei Zhang, Yan Wang, Yuehong Cui, Qian Li, Tianshu Liu
Journal: Journal of Clinical Oncology (2022)

e16094 Background: Hepatoid adenocarcinoma (HAC) is a rare pathological subtype of extrahepatic tumor, featured by hepatoid differentiation and α-fetoprotein (AFP)-production. Hepatoid adenocarcinoma of the stomach (HAS), accounting for 0.17 to 15% of gastric cancers, is the most common subtype of HAC, and has attracted increasing attention duo to its high degree of malignancy. Compared with classic gastric cancer (GC), HAS showed a higher rate of vascular invasion, lymph node metastasis, and liver metastasis, with only 9% survival at 5 years. In this study, we aim to investigate the molecular features of HAS and identify the potential therapeutic targets for HAS. Methods: We conducted whole-exome sequencing (WES) of 40 paired tumor and normal samples, including 25 HAS, 6 HAC of other organ and 9 AFP-producing gastric cancer (AFPGC). All patients underwent radical surgery at Shanghai Zhongshan Hospital between July 2013 and September 2017. qRT-PCR, Western blot and immunohistochemistry were detected to explore MUC19 expression in HAS. CCK8 assay, Transwell assay, immunofluorescence assay and subcutaneous xenograft tumor model were used to detect functional effects and the mechanism of MUC19. Results: In HAS patients, the top 5 frequently mutated genes were TP53 (44%), TTN (44%), MUC19 (40%), CCNE1 (28%) and CDC27 (28%). Further compared with TCGA datasets, MUC19, CCNE1, CDC27 mutations were almost undetectable in STAD, CRC and HCC. In terms of CNV analysis, VSTM2B, PLEKHF1, POP4, URI1 and TERT were the most frequently amplificated genes in HAS tumor tissues. Interestingly, amplification of 4 genes (VSTM2B, CCNE1, LEKHF1, POP4), which located in chr19q12, was significantly associated with poor prognosis. The tumor mutational burden (TMB) levels and AFP expression of HAS and AFPGC patients were no significantly different, while patients with higher TMB had a remarkably longer overall survival ( p= 0.0065). Moreover, we found MUC19 expression was positively correlated with AFP levels in HAS and MUC19 promoted the transcription of AFP in GC cells. Mechanistically, MUC19 contributed to the aggressive malignancy phenotypes of GC cells through activating the Wnt/β-catenin signaling pathway. Conclusions: MUC19 may be a potential target for HAS diagnosis and treatment. Amplification of genes located in chr19q12 occurred frequently in HAS and were associate with poor prognosis. TMB was sensitive for the overall survival of HAS patients.